Prion Diseases¶
Chapter 449 | Part 13: Neurologic Disorders · Part 13 – Neurologic Disorders · Chapter 449
Key Clinical Points¶
- Prions are unique infectious agents that lack nucleic acid (DNA/RNA) and consist of proteinaceous particles.
- The core pathology is the conversion of cellular prion protein (PrP^C) into the disease-causing scrapie isoform (PrP^{Sc}).
- Sporadic CJD (sCJD) accounts for ~85% of human cases; Variant CJD (vCJD) affects younger patients with a psychiatric prodrome.
- Iatrogenic CJD (iCJD) results from medical procedures involving contaminated tissues or hormones.
- The PrP^{Sc} isoform is characterized by high β-structure and resistance to limited proteolysis, forming the PrP^{27-30} fragment.
- Genetic mutations in the PRNP gene (chromosome 20) lead to familial CJD, GSS, and FFI.
- Codon 129 polymorphisms (M/V) significantly influence the clinical phenotype and age of onset of sCJD.
- Neuroimaging for CJD typically shows 'cortical ribboning' and basal ganglia hyperintensity on DWI/FLAIR.
- Prion diseases are distinguished from other neurodegenerative disorders like PLS and HSP by their rapid progression and specific pathology.
- Specific polymorphisms (e.g., at codons 219, 171, and 127) have been identified as conferring resistance to certain prion strains.
DEFINITION & CLASSIFICATION¶
• Prion Definition:
Definition (Harrison's 22e): Prions are proteins that adopt alternative conformations, which become self-propagating. • Molecular Basis: PrP is the human prion protein; PrP^C is the normal cellular isoform (high α-helix), while PrP^{Sc} is the disease-causing scrapie isoform (high β-structure). • Mechanism of Infection: PrP^{Sc} acts as a template → converts PrP^C into nascent PrP^{Sc}. • Proteolysis: Limited proteolysis of PrP^{Sc} produces PrP^{27-30} (approx. 142 amino acids); PrP^C is completely hydrolyzed. • Classification of Human Diseases: Sporadic CJD (sCJD): Most common (~85% of cases). Genetic Prion Diseases: 10–15% of cases; include familial CJD (fCJD), Gerstmann-Sträussler-Scheinker (GSS) disease, and fatal familial insomnia (FFI). Infectious/Iatrogenic CJD (iCJD): <1% of cases; acquired via medical procedures (e.g., cadaver-derived dura mater, pituitary hormones, corneal transplants).
EPIDEMIOLOGY¶
• Incidence & Risk: sCJD Incidence: ~1–2 cases per million population. Lifetime Risk: 1 in 5,000 to 6,000 deaths. • Demographics: sCJD: Age-dependent; incidence expected to increase as older populations grow. vCJD: Affects younger patients (mean age 28 years). • Geographic/Environmental Factors: Clusters: Often linked to specific PRNP mutations or misdiagnoses rather than common environmental exposure. _Wildlife:* CDC monitors CWD in deer; up to 90% of culled deer in some herds may harbor CWD prions.
ETIOLOGY & PATHOPHYSIOLOGY¶
• Pathogenesis Mechanisms: Scenario 1: Somatic mutation in a single cell → mutated PrP^C more susceptible to misfolding into PrP^{Sc}. Scenario 2: Spontaneous crossing of the activation energy barrier between PrP^C and PrP^{Sc} (more likely in older individuals). Scenario 3: PrP^{Sc} exists at low levels in normal cells; metabolic changes lead to accumulation exceeding clearance capacity. • Species Barrier: Mechanism: Transmission efficiency depends on the degree of similarity between host and donor PrP sequence. Significance: Suggests PrP^C directly interacts with PrP^{Sc} during conversion. • Genetic Polymorphisms: Codon 129 (M/V): Influences age of onset and clinical phenotype. Codon 219: Substitution of Lysine for Glutamine in humans; 12% of population appears resistant to prion disease. Codon 171: Arginine substitution provides resistance to scrapie but susceptibility to BSE. Codon 127: Identified in long-term survivors of the kuru epidemic; confers protection against prion disease.
CLINICAL FEATURES¶
• General Presentation: Rapidly progressive dementia → motor abnormalities → behavioral changes. Progression: Typically fatal within ~7 months of onset. Prodrome: Seen in 1/3 of patients; includes fatigue, sleep disturbance, weight loss, headache, anxiety, vertigo, and malaise. • Specific Variants: Heidenhain Variant: Early isolated visual impairment. Brownell-Oppenheim Variant: Early cerebellar gait and coordination deficits. • Sporadic CJD (sCJD) Subtypes: MM1/MV1: Most common (40–70%); rapid dementia, ataxia, myoclonus; mean survival 4–7 months. VV2: ~15% of cases; starts with ataxia; similar survival to MM1/MV1. MV2: ~10% of cases; includes MV2K (kuru plaques in cerebellum) and MV2C (cortical subtype). MM2: ~4% of cases; divided into MM2T (thalamic, similar to FFI) and MM2C (cortical, slower progression). VV1: ~1% of cases; mean age of onset in mid-to-late 40s. • Variant CJD (vCJD): Prodrome: Early psychiatric symptoms (depression, anxiety, apathy) for several months before neurological signs. Neurological Symptoms: Cerebellar ataxia, painful sensory symptoms, myoclonus/dystonia/chorea. Demographics: Mean age of onset 28 years; majority <55 years old. • Iatrogenic CJD (iCJD): Transmission Sources: Cadaver-derived dura mater, human pituitary hormones, corneal transplants, and contaminated EEG electrodes.
DIFFERENTIAL DIAGNOSIS¶
• Primary Lateral Sclerosis (PLS): Clinical: Progressive spastic weakness of limbs; spastic dysarthria/dysphagia. Distinction: No denervation on EMG or muscle biopsy; no sensory changes. Course is usually indolent compared to CJD. • Hereditary Spastic Paraplegia (HSP): _Clinical: Progresses in 3rd/4th decade; spastic weakness of lower extremities; often includes posterior column abnormalities. _Distinction: Long survival; typically autosomal trait; distinct genetic markers (e.g., spastin gene).
DIAGNOSTIC APPROACH¶
- Laboratory Testing for PrP^{Sc}: Method: Limited proteolysis to generate PrP^{27-30}. Detection: Immunoassay after denaturation. Note: Brain biopsy is definitive but rarely indicated due to availability of other tests.
- Neuroimaging (MRI): Sequence:* Look for hyperintensity on T2/FLAIR and DWI. _Finding 1: 'Cortical ribboning' (restricted diffusion in the cerebral cortex). Finding 2: Basal ganglia involvement (caudate head and putamen). Confirmation: Use ADC maps to confirm that hyperintensities are due to restricted diffusion, not artifacts.
MANAGEMENT & TREATMENT¶
- Iatrogenic Prevention: Action:* Avoid use of high-risk materials (e.g., cadaver-derived dura mater, human pituitary hormones). _Current Standard: Recombinant human growth hormone (hGH) is used exclusively to prevent prion contamination.
- Clinical Management: _Observation: Monitor progression of dementia and motor symptoms. _Prognosis: Generally poor; death typically occurs within 7 months for sCJD.
KEY PEARLS & HIGH-YIELD POINTS¶
• Prion Definition:
Definition (Harrison's 22e): Prions are proteins that adopt alternative conformations, which become self-propagating. • Key Biomarker: PrP^{27-30} is the protease-resistant fragment used to identify PrP^{Sc}. • Imaging Hallmark: 'Cortical ribboning' and basal ganglia hyperintensity on DWI are highly characteristic of CJD. • Clinical Distinction: vCJD presents with a psychiatric prodrome in younger patients; sCJD is typically an older population with rapid progression.
TABLES & FIGURES¶
• Table 449-1 (Glossary): Prion: Proteinaceous infectious particle lacking nucleic acid. PrPSc: Disease-causing scrapie isoform; only identifiable macromolecule in purified preparations. PrPC: Cellular precursor of PrPSc. PrP 27-30: Fragment resulting from limited proteolysis; retains infectivity and forms amyloid. PRNP: Gene on chromosome 20. Prion rod: Aggregate of prions (mostly PrP^{27-30}). PrP amyloid: Accumulates as plaques in brain tissue.
• Table 449-2 (Diseases): Human Diseases: Kuru, iCJD, vCJD, fCJD, GSS, FFI, sCJD, sFI. Animal Diseases: Scrapie (sheep/goats), BSE (cattle), TME (mink), CWD (deer/elk/moose), FSE (cats), Exotic ungulate encephalopathy.
• Table 449-3 (Mice Study): FFI to Mouse: Incubation of 206 ± 7 days (7/7) and 136 ± 1 days (6/6). fCJD to Mouse: Incubation of 170 ± 2 days (10/10) and 167 ± 3 days (15/15).
• Figure 449-1: Illustrates the starburst pattern of PrP^{Sc} accumulation in neural tissue. • Figure 449-2: Shows the processing from a 254-amino acid precursor to PrP^C (209 aa) and PrP^{27-30} (~142 aa). • Figure 449-3: Demonstrates the diagnostic value of MRI in identifying cortical ribboning and basal ganglia involvement.
Reference Tables¶
TABLE 449-2 The PrP Prion Diseases DISEASE Human Kuru iCJD vCJD fCJD¶
Harrison's 22e, p.3526
| Prion | Proteinaceous infectious particle that lacks nucleic acid. Prions are composed entirely of alternatively folded proteins that undergo self-propagation. Distinct strains of prions exhibit different biologic properties, which are epigenetically heritable. PrP prions cause scrapie in sheep and goats, mad cow disease, and related neurodegenerative diseases of humans such as Creutzfeldt-Jakob disease (CJD). |
|---|---|
TABLE 449-2 The PrP Prion Diseases
| DISEASE | HOST | MECHANISM OF PATHOGENESIS |
|---|---|---|
| Human | ||
| Fore people | ||
| iCJD | Humans | Infection from prion-contaminated hGH, dura mater grafts, etc. |
| Humans | ||
| fCJD | Humans | Germline mutations in PRNP |
| Humans | ||
| FFI | Humans | Germline mutation in PRNP (D178N, M129) |
| Humans | ||
| sFI | Humans | Somatic mutation or spontaneous conversion of PrPC into PrPSc? |
| PrPC | Cellular isoform of the prion protein. PrPC is the precursor of PrPSc. | |
| PRNP | PrP gene located on human chromosome 20. | |
| Scrapie | Sheep, goats | Infection in genetically susceptible sheep and goats |
| Cattle | ||
| TME | Mink | Infection with prions from sheep or cattle |
| Mule deer, elk, or moose |
||
| FSE | Cats | Infection with prion-contaminated beef |
| Greater kudu, nyala, or oryx |
||
| PrP amyloid | Amyloid containing PrP in the brains of animals or humans with prion disease; often accumulates as plaques. |
TABLE 449-3 Distinct Prion Strains Generated in Humans with Inherited Prion Diseases and Transmitted to Transgenic Mice…¶
Harrison's 22e, p.3528
| INOCULUM | HOST SPECIES | HOST PrP GENOTYPE | INCUBATION TIME [DAYS ± SEM] (n/n) 0 |
PrPSc (kDa) |
|---|---|---|---|---|
| None | Human | FFI(D178N, M129) | 19 | |
| Mouse | Tg(MHu2M) | 206 ± 7 (7/7) | ||
| FFI → Tg(MHu2M) | Mouse | Tg(MHu2M) | 136 ± 1 (6/6) | 19 |
| Human | fCJD(E200K) | |||
| fCJD | Mouse | Tg(MHu2M) | 170 ± 2 (10/10) | 21 |
| Mouse | Tg(MHu2M) | 167 ± 3 (15/15) |